Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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and patients [ 61 , 73 , 94 , 136 , 143 ]. These discrepancies could result from differ-

ences in the intensity, duration and type of the exercise protocol used [ 169 ].

Therefore, the beneficial effects of exercise training on myocardial remodeling and

function seems to be only mild. Nonetheless, exercise training is capable improve

other deficits induced by HF.

The impaired coronary blood flow and coronary reserve in HF are improved by

exercise training, which activates myocardial angiogenesis [ 87 , 143 ]. This finding is

of relevance since the high coronary flow reserve has significant prognostic value in

the context of HF [ 132 ]. Decreased coronary blood flow in HF is related to an

increased production of reactive oxygen species in the coronary arteries and

decreased levels of antioxidant enzymes [ 31 ], leading to increased NO scavenging

and impaired endothelial NO synthase (NOS) function [ 16 , 168 ]. Excessive oxida-

tive stress, as demonstrated by increased levels of reactive oxygen species and

decreased levels of antioxidant enzymes, also affects the myocardium itself [ 65 , 66 ,

70 ]. The consequences of this dysfunction is the injury of cardiomyocytes, with

contractile abnormalities [ 72 ], impairment of the proteasome, leading to accumula-

tion of misfolded proteins [ 46 ], and eventually culminating in cell death. Exercise

training induces cardioprotection through the reduction in oxidative stress simulta-

neously with the increase of antioxidant enzymes [ 12 ], thus restoring the cellular

protein quality control [ 29 ].

Another feature of HF is impaired Ca2+ handling. The calcium homeostasis

within cardiomyocytes is regulated by several proteins. Special attention has been

given to those responsible for the control of the Ca2+ uptake and release within the

sarcoplasm and sarcolemma. Those include the sarcoplasmic reticulum Ca2+ATPase

(SERCA2) and its regulator phospholamban (PLN), the ryanodine receptor, Ca2+

channels, and the Na+/Ca2+ exchanger. While it is consensual that HF leads to Ca2+

handling dysfunction and excitation-contraction uncoupling, the mechanisms lead-

ing to those alterations are very complex and studies show conflicting results [ 11 ,

98 ]. Nonetheless, it seems that exercise training is able to ameliorate the HF-induced

Ca2+ handling alterations, whichever directions they occur [ 76 , 101 , 134 , 152 , 170 ].

The heart in HF, submitted to excessive sympathetic signaling, show β-adrenergic

receptor desensitization [ 56 ]. This results from a reduction in the density of β 1 -

adrenergic receptor, a decreased β 1 / β 2 ratio [ 26 ] and uncoupling of β 1 -adrenergic

receptor from the Gs protein caused by enhanced βARK expression [ 156 ]. Exercise

training can attenuate this desensitization thus increasing β-adrenergic response

[ 87 ], likely through increases in the expression of β 1 -adrenergic receptors and

cAMP levels [ 38 , 87 ]. Therefore, exercise training can restore cardiac contractility

reserve in HF.

HF also results in a dysfunction of the sinus node pacemaker cells leading to

decreased intrinsic pacemaker heart rate (see Fig. 11.1) [ 69 , 141 , 174 ]. This sinus

node dysfunction is characterized by increased recovery time and intrinsic cycle

length, a caudal shift of the pacemaker location and slower sinoatrial conduction

[ 141 ]. Molecular alterations that might explain these alterations include widespread

changes in the expression of ion channels, gap junction channels, Ca2+, Na+, and

H+-handling proteins and receptors [ 174 ]. This sinus node dysfunction, along with

M.H.A. Ichige et al.